Browsing by Author "Martinez, Fernando D."

Now showing 1 - 5 of 5
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    Childhood Asthma Incidence, Early and Persistent Wheeze, and Neighborhood Socioeconomic Factors in the ECHO/CREW Consortium
    (American Medical Association, 2022) Zanobetti, Antonella; Ryan, Patrick H.; Coull, Brent; Brokamp, Cole; Datta, Soma; Blossom, Jeffrey; Lothrop, Nathan; Miller, Rachel L.; Beamer, Paloma I.; Visness, Cynthia M.; Andrews, Howard; Bacharier, Leonard B.; Hartert, Tina; Johnson, Christine C.; Ownby, Dennis; Khurana Hershey, Gurjit K.; Joseph, Christine; Yiqiang, Song; Mendonça, Eneida A.; Jackson, Daniel J.; Luttmann-Gibson, Heike; Zoratti, Edward M.; Wright, Anne L.; Martinez, Fernando D.; Seroogy, Christine M.; Gern, James E.; Gold, Diane R.; Children’s Respiratory and Environmental Workgroup (CREW) Consortium; Epidemiology, School of Public Health
    Importance: In the United States, Black and Hispanic children have higher rates of asthma and asthma-related morbidity compared with White children and disproportionately reside in communities with economic deprivation. Objective: To determine the extent to which neighborhood-level socioeconomic indicators explain racial and ethnic disparities in childhood wheezing and asthma. Design, setting, and participants: The study population comprised children in birth cohorts located throughout the United States that are part of the Children's Respiratory and Environmental Workgroup consortium. Cox proportional hazard models were used to estimate hazard ratios (HRs) of asthma incidence, and logistic regression was used to estimate odds ratios of early and persistent wheeze prevalence accounting for mother's education, parental asthma, smoking during pregnancy, child's race and ethnicity, sex, and region and decade of birth. Exposures: Neighborhood-level socioeconomic indicators defined by US census tracts calculated as z scores for multiple tract-level variables relative to the US average linked to participants' birth record address and decade of birth. The parent or caregiver reported the child's race and ethnicity. Main outcomes and measures: Prevalence of early and persistent childhood wheeze and asthma incidence. Results: Of 5809 children, 46% reported wheezing before age 2 years, and 26% reported persistent wheeze through age 11 years. Asthma prevalence by age 11 years varied by cohort, with an overall median prevalence of 25%. Black children (HR, 1.47; 95% CI, 1.26-1.73) and Hispanic children (HR, 1.29; 95% CI, 1.09-1.53) were at significantly increased risk for asthma incidence compared with White children, with onset occurring earlier in childhood. Children born in tracts with a greater proportion of low-income households, population density, and poverty had increased asthma incidence. Results for early and persistent wheeze were similar. In effect modification analysis, census variables did not significantly modify the association between race and ethnicity and risk for asthma incidence; Black and Hispanic children remained at higher risk for asthma compared with White children across census tracts socioeconomic levels. Conclusions and relevance: Adjusting for individual-level characteristics, we observed neighborhood socioeconomic disparities in childhood wheeze and asthma. Black and Hispanic children had more asthma in neighborhoods of all income levels. Neighborhood- and individual-level characteristics and their root causes should be considered as sources of respiratory health inequities.
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    Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood
    (American Thoracic Society, 2021) Hallmark, Brian; Wegienka, Ganesa; Havstad, Suzanne; Billheimer, Dean; Ownby, Dennis; Mendonca, Eneida A.; Gress, Lisa; Stern, Debra A.; Biagini Myers, Jocelyn; Khurana Hershey, Gurjit K.; Hoepner, Lori; Miller, Rachel L.; Lemanske, Robert F.; Jackson, Daniel J.; Gold, Diane R.; O’Connor, George T.; Nicolae, Dan L.; Gern, James E.; Ober, Carole; Wright, Anne L.; Martinez, Fernando D.; ECHO-CREW; Pediatrics, School of Medicine
    Rationale: Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored. Objectives: To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry. Methods: Data from seven U.S. birth cohorts (n = 3,786) from the CREW (Children’s Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) (n = 1,308) and, for the first time, in African American (AA) (n = 620) children. Measurements and Main Results: The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children. Conclusions: These results indicate that 17q12-21 is a “wheezing locus,” and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.
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    Geography, generalisability, and susceptibility in clinical trials
    (Elsevier, 2021) Clougherty, Jane E.; Kinnee, Ellen J.; Cardet, Juan Carlos; Mauger, David; Bacharier, Leonard; Beigelman, Avraham; Blake, Kathryn V.; Cabana, Michael D.; Castro, Mario; Chmiel, James F.; Covar, Ronina; Fitzpatrick, Anne; Gaffin, Jonathan M.; Gentile, Deborah; Israel, Elliot; Jackson, Daniel J.; Kraft, Monica; Krishnan, Jerry A.; Kumar, Harsha Vardhan; Lang, Jason E.; Lazarus, Stephen C.; Lemanske, Robert F.; Lima, John; Martinez, Fernando D.; Morgan, Wayne; Moy, James; Myers, Ross; Naureckas, Edward T.; Ortega, Victor E.; Peters, Stephen P.; Phipatanakul, Wanda; Pongracic, Jacqueline A; Ross, Kristie; Sheehan, William J.; Smith, Lewis J.; Solway, Julian; Sorkness, Christine A.; Wechsler, Michael E.; Wenzel, Sally; White, Steven R.; Holguin, Fernando; Pediatrics, School of Medicine
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    PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment
    (Elsevier, 2021) Israel, Elliot; Denlinger, Loren C.; Bacharier, Leonard B.; LaVange, Lisa M.; Moore, Wendy C.; Peters, Michael C.; Georas, Steve N.; Wright, Rosalind J.; Mauger, David T.; Noel, Patricia; Akuthota, Praveen; Bach, Julia; Bleecker, Eugene R.; Cardet, Juan Carlos; Carr, Tara F.; Castro, Mario; Cinelli, Angeles; Comhair, Suzy A.A.; Covar, Ronina A.; Alexander, Laura Crotty; DiMango, Emily A.; Erzurum, Serpil C.; Fahy, John V.; Fajt, Merritt L.; Gaston, Benjamin M.; Hoffman, Eric A.; Holguin, Fernando; Jackson, Daniel J.; Jain, Sonia; Jarjour, Nizar N.; Ji, Yuan; Kenyon, Nicholas J.; Kosorok, Michael R.; Kraft, Monica; Krishnan, Jerry A.; Kumar, Rajesh; Liu, Andrew H.; Liu, Mark C.; Ly, Ngoc P.; Marquis, M. Alison; Martinez, Fernando D.; Moy, James N.; O’Neal, Wanda K.; Ortega, Victor E.; Peden, David B.; Phipatanakul, Wanda; Ross, Kristie; Smith, Lewis J.; Szefler, Stanley J.; Teague, W. Gerald; Tulchinsky, Abigail F.; Vijayanand, Pandurangan; Wechsler, Michael E.; Wenzel, Sally E.; White, Steven R.; Zeki, Amir A.; Ivanova, Anastasia; Pediatrics, School of Medicine
    Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.
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    Preventing asthma in high risk kids (PARK) with omalizumab: Design, rationale, methods, lessons learned and adaptation
    (Elsevier, 2021-01) Phipatanakul, Wanda; Mauger, David T.; Guilbert, Theresa W.; Bacharier, Leonard B.; Durrani, Sandy; Jackson, Daniel J.; Martinez, Fernando D.; Fitzpatrick, Anne M.; Cunningham, Amparito; Kunselman, Susan; Wheatley, Lisa M.; Bauer, Cindy; Davis, Carla M.; Geng, Bob; Kloepfer, Kirsten M.; Lapin, Craig; Liu, Andrew H.; Pongracic, Jacqueline A.; Teach, Stephen J.; Chmiel, James; Gaffin, Jonathan M.; Greenhawt, Matthew; Gupta, Meera R.; Lai, Peggy S.; Lemanske, Robert F.; Morgan, Wayne J.; Sheehan, William J.; Stokes, Jeffrey; Thorne, Peter S.; Oettgen, Hans C.; Israel, Elliot; Pediatrics, School of Medicine
    Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma – viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2–3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.